title: Hypoxic human cancer cells are sensitized  to BH-3 mimetic–induced apoptosis via  downregulation of the Bcl-2 protein Mcl-1.
abstract: Solid tumors contain hypoxic regions in which cancer cells are often resistant to chemotherapy-induced apoptotic cell death. Therapeutic strategies that specifically target hypoxic cells and promote apoptosis are particularly appealing, as few normal tissues experience hypoxia. We have found that the compound ABT-737, a Bcl-2 homology domain 3 (BH-3) mimetic, promotes apoptotic cell death in human colorectal carcinoma and small cell lung cancer cell lines exposed to hypoxia. This hypoxic induction of apoptosis was mediated through downregulation of myeloid cell leukemia sequence 1 (Mcl-1), a Bcl-2 family protein that serves as a biomarker for ABT-737 resistance. Downregulation of Mcl-1 in hypoxia was independent of hypoxia-inducible factor 1 (HIF-1) activity and was consistent with decreased global protein translation. In addition, ABT-737 induced apoptosis deep within tumor spheroids, consistent with an optimal hypoxic oxygen tension being necessary to promote ABT-737–induced cell death. Tumor xenografts in ABT-737–treated mice also displayed significantly more apoptotic cells within hypoxic regions relative to normoxic regions. Synergies between ABT-737 and other cytotoxic drugs were maintained in hypoxia, suggesting that this drug may be useful in combination with chemotherapeutic agents. Taken together, these findings suggest that Mcl-1–sparing BH-3 mimetics may induce apoptosis in hypoxic tumor cells that are resistant to other chemotherapeutic agents and may have a role in combinatorial chemotherapeutic regimens for treatment of solid tumors.
authors.affiliation: Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.
authors.forename: Luke R E
authors.initials: LR
authors.lastname: Harrison
authors.forename: Dimitra
authors.initials: D
authors.lastname: Micha
authors.forename: Martin
authors.initials: M
authors.lastname: Brandenburg
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Simpson
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Morrow
authors.forename: Olive
authors.initials: O
authors.lastname: Denneny
authors.forename: Cassandra
authors.initials: C
authors.lastname: Hodgkinson
authors.forename: Zaira
authors.initials: Z
authors.lastname: Yunus
authors.forename: Clare
authors.initials: C
authors.lastname: Dempsey
authors.forename: Darren
authors.initials: D
authors.lastname: Roberts
authors.forename: Fiona
authors.initials: F
authors.lastname: Blackhall
authors.forename: Guy
authors.initials: G
authors.lastname: Makin
authors.forename: Caroline
authors.initials: C
authors.lastname: Dive
mesh_terms: D000818:Animals; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000860:Hypoxia; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D009596:Nitrophenols / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C501332:ABT-737; C474007:Bax protein (53-86); D001713:Biphenyl Compounds; C579095:MCL1 protein, human; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides